This project will determine the effect of aging on alveolar macrophages (AMs) and their interaction with M.tb. We will address how alterations in AM biology during aging impact the increased risk of the elderly to airborne infection, a greatly underexplored area. AMs are classified as alternatively activated macrophages or, more generally, immunoregulatory macrophages that enable clearance of aerosolized particulates while maintaining optimal gas exchange. The studies herein are based on the emerging concept that with aging chronic low- grade inflammation (inflammaging) occurs in the lung which alters AM phenotype and function. Our central hypothesis is that chronic lung inflammation during aging is associated with a unique inflammatory signature which paradoxically leads to early control of M.tb in AMs, while setting the stage for subsequent enhanced growth and bacterial dissemination. We put forth the novel hypothesis that this occurs through uncontrolled activation of a specific macrophage immunoregulatory network resulting in enhanced cellular immigration to the lungs, AM activation and pathology. The consequences of the different inflammatory sequences in the young vs. old is that in the young, the immunoregulatory signature results in establishment of latency with stable granulomas containing fewer M.tb and immune cells. In contrast, in the elderly the long-term effects of the chronic inflammation are establishment of latency with unstable granulomas containing more M.tb and activated immune cells that drive reactivation. We have developed a new three stage model to be explored in 3 specific aims: 1) Define age-related phenotype and immune function of AMs (Stage 1). Expression of specific receptors, inflammatory modulators and oxidants will be compared in adult/elderly human and young/old mouse AMs. We will define the initial signaling pathways that regulate cytokine production and determine if old age increases recruitment and retention of activated AMs in the lung. 2) Determine AM uptake and control of M.tb in old age while initiating an aberrant inflammatory signaling network (Stages 2 and 3). We will compare phagocytosis, oxidative responses, trafficking and intracellular growth of M.tb in AMs in old vs. young age. We will also characterize an alternative NF-??1-mediated signaling pathway in AMs from the elderly which, during M.tb infection, leads to increased IL-10, and activation of an IFN-?/? autocrine feedback loop that sustains IL- 10 and CCL2 production. 3) Define the impact of the AM aberrant inflammatory signaling network during the course of infection in old mice, including reactivation (Stage 3). We will determine activity of the aberrant signaling network during the course of in vivo infection of old mice. We will also assess the importance of specific signaling network components on enhanced M.tb growth in old mice using blockers. The project fully integrates with and informs the other projects and cores. The proposed studies are innovative in that they provide the first comprehensive, model-driven, comparative and mechanistic analyses of the effects of aging on human and mouse AM function in old age.